Epilepsy after the first drug fails: substitution or add-on?

When and how a combination of antiepileptic drugs (AEDs) should be used in patients unresponsive to monotherapy is not known. We followed up prospectively 248 patients in whom treatment with the first AED was unsuccessful. When treatment failed due to intolerable adverse events, a second (substituted) drug was prescribed. When failure was due to lack of efficacy, either AED substitution or combination (add-on) was undertaken. Patients were considered to be seizure-free if they had no seizures for at least 1 year. Among patients with inadequate seizure control on the first well tolerated AED, those who received substituted monotherapy (n= 35) and those who received add-on treatment (n= 42) had similar seizure-free rates (substitution vs. add-on: 17% vs. 26%) and incidence of intolerable side effects (substitution vs. add-on: 26% vs. 12%). Based on the drugs' perceived primary mode of action, more patients became seizure-free when the combination involved a sodium channel blocker and a drug with multiple mechanisms of action (36%) compared to other combinations (7 %, P= 0.05). None of the 11 patients who received add-on treatment after a second drug had also failed became seizure-free, compared to 26% in those who received add-on as soon as the first tolerated AED proved to be ineffective (n= 42, P= 0.05). These preliminary observations have generated verifiable hypotheses regarding the early management of epilepsy. A randomized study comparing substitution and combination after the failure of the first AED is underway.

[1]  M. Brodie,et al.  New antiepileptic drugs , 1997 .

[2]  I. Fried,et al.  Long‐term follow‐up after temporal lobe resection for lesions associated with chronic seizures , 1997, Neurology.

[3]  S. Shinnar,et al.  Long-term prognosis of seizures with onset in childhood. , 1998, The New England journal of medicine.

[4]  J. Engel,et al.  The timing of surgical intervention for mesial temporal lobe epilepsy: a plan for a randomized clinical trial. , 1999, Archives of neurology.

[5]  S. Shorvon,et al.  Monotherapy or polytherapy for epilepsy? , 1981, Epilepsia.

[6]  S. Shorvon,et al.  Reduction in polypharmacy for epilepsy. , 1979, British medical journal.

[7]  M. Brodie,et al.  Lamotrigine substitution study: evidence for synergism with sodium valproate? , 1997, Epilepsy Research.

[8]  D. Schmidt.  Reduction of Two‐Drug Therapy in Intractable Epilepsy , 1983, Epilepsia.

[9]  M. J. Brodie,et al.  Drug therapy : antiepileptic drugs , 1996 .

[10]  R. Macdonald,et al.  Antiepileptic Drug Mechanisms of Action , 1993, Epilepsia.

[11]  Josemir W Sander,et al.  Some Aspects of Prognosis in the Epilepsies: A Review , 1993, Epilepsia.

[12]  A. Guberman.  Monotherapy or Polytherapy for Epilepsy? , 1998, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[13]  P. Kwan,et al.  Early identification of refractory epilepsy. , 2000, The New England journal of medicine.

[14]  E. Perucca,et al.  The Efficacy of Valproate‐Lamotrigine Comedication in Refractory Complex Partial Seizures: Evidence for a Pharmacodynamic Interaction , 1999, Epilepsia.

[15]  J. Cramer,et al.  A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. , 1992, The New England journal of medicine.

[16]  Y Langan,et al.  Sudden unexpected death in epilepsy , 1999, Postgraduate medical journal.

[17]  S. Shorvon,et al.  Monotherapy or Poly therapy for Epilepsy? , 1981 .

[18]  M. Brodie,et al.  Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy , 1995, The Lancet.

[19]  M. Brodie,et al.  Monostars: An Aid to Choosing an Antiepileptic Drug as Monotherapy , 1999, Epilepsia.

[20]  G. Holmes,et al.  Mesial temporal sclerosis: pathogenesis and significance. , 1995, Pediatric neurology.

[21]  A. Richens,et al.  A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG Collaborative Group. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[22]  D. Schmidt.  Two antiepileptic drugs for intractable epilepsy with complex-partial seizures. , 1982, Journal of neurology, neurosurgery, and psychiatry.

[23]  E. Tobias,et al.  An outcome audit at the epilepsy clinic: results from 1000 consecutive referrals , 1994, Seizure.

[24]  E. So,et al.  The Cost of Epilepsy in the United States: An Estimate from Population‐Based Clinical and Survey Data , 2000, Epilepsia.

[25]  H. S. Bennett,et al.  REDUCTION OF POLYPHARMACY FOR EPILEPSY IN AN INSTITUTION FOR THE RETARDED , 1983, Developmental medicine and child neurology.

[26]  Smith,et al.  Epilepsy and other Chronic Convulsive Diseases, Their Causes, Symptoms and Treatment , 1902 .

[27]  M. Brodie,et al.  Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. , 1995, Lancet.

[28]  B. Meldrum.  Update on the Mechanism of Action of Antiepileptic Drugs , 1996, Epilepsia.

[29]  Five Years of Anticonvulsant Monitoring on Site at the Epilepsy Clinic , 1993, Therapeutic drug monitoring.

[30]  D. Schmidt,et al.  Monotherapy versus Polytherapy in Epilepsy , 1995 .

[31]  A. Beydoun.  Monotherapy Trials of New Antiepileptic Drugs , 1997, Epilepsia.

[32]  A. Lockhart Gillespie,et al.  Epilepsy and Other Chronic Convulsive Diseases: Their Causes, Symptoms, and Treatment , 1902, Edinburgh Medical Journal.

[33]  M. Dragunow,et al.  Neurochemical and morphological changes associated with human epilepsy , 1995, Brain Research Reviews.

[34]  S Shinnar,et al.  Do seizures beget seizures? An assessment of the clinical evidence in humans. , 1997, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[35]  Ingmar Blümcke,et al.  Molecular neuropathology of human mesial temporal lobe epilepsy , 1999, Epilepsy Research.

[36]  A. Marson,et al.  New antiepileptic drugs: a systematic review of their efficacy and tolerability , 1996, BMJ.

[37]  O. Devinsky.  Cognitive and Behavioral Effects of Antiepileptic Drugs , 1995, Epilepsia.

[38]  S. Shorvon,et al.  Unnecessary polypharmacy for epilepsy. , 1977, British medical journal.

[39]  M. Brodie,et al.  Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy , 1999, Epilepsy Research.

[40]  W. Löscher,et al.  Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations , 1988, Epilepsy Research.

[41]  M. Brodie,et al.  Management of epilepsy in adolescents and adults , 2000, The Lancet.